Rebamipide or the salt thereof, which is an active ingredient in the aqueous suspension of the invention, is known as a useful antiulcer drug. In addition, rebamipide has an increasing action of goblet cell density in eye, an increasing action of mucus in eye, and an increasing action of lacrimal fluid, and has been already known as an agent for treating dry eye, i.e. dry eye syndrome (JP-A-9-301866).
Sugimoto and Hirakawa reported on a method for providing a fine-grained crystal, which comprises neutralizing a water-soluble salt given from an insoluble acid compound and a base with an acid in the presence of a polymer compound and/or a surfactant (JP-A-50-121424). In addition, Hirakawa et al. detailedly reported on a micronization of oxolinic acid through the above process [YAKUGAKU ZASSHI 102(10) 951-959 (1982), ibidem 103(6) 690-695 (1983), ibidem 103(11) 1215-1218 (1983), and ibidem 103(11) 1190-1194 (1983)]. Furthermore, Hirakawa et al. reported that they managed to micronize phenyloin and phenobarbital to only at maximum 3 to 4 μm of the average particle size through the above process [YAKUGAKU ZASSHI 104(1) 91-96 (1984)]. Sato et al. also reported on a method for micronizing an insoluble compound which is soluble with acid or base, by means of neutralization (JP-A-55-139319).
Pranab Bagchi et al. reported on a method for preparing a nanoparticle, which comprises dissolving a pharmaceutical compound with a base and neutralizing it with an acid in the presence of a surface-modifying agent and a surface-activating agent (U.S. Pat. Nos. 5,560,932, 5,662,883, 5,665,331, and 5,716,642).
As mentioned above, the method for preparing a fine-grained crystal, which comprises neutralizing a water-soluble salt given from an acid compound and a base with an acid in the presence of a polymer compound and/or a surfactant, is a known prior art. However, as shown in the above examples of phenyloin and phenobarbital, the micronized size may largely depend on the type of compound, so it is hard to predict it. Besides, there were not any similar reports about rebamipide until now. In general, even if the micronization is led to sub-micron level, the suspension will exhibit a white milky feature; accordingly there has not been any report about a method to prepare a solution having a high transparency suitable for ophthalmic use as disclosed in the invention. Further, there has not been any report about a method to prepare a suspension having a surprisingly high transparency by the way that the pH of the suspension prepared by crystallization is adjusted to 3-7 and then the mixture is stirred and/or dispersed. Furthermore, there has not been any report about a method to prepare a suspension having a markedly more improved transparency by additional dialyzing process. Additionally, there has not been any report about a method to prepare a needle crystal of rebamipide having a ratio between the long gage length and the short gage length is not less than 4, which exhibit a specific transparency.